Process for the synthesis of pergolide

ABSTRACT

A process for the synthesis of pergolide (Formula (1)) (D-6-n-propyl-8βmethylmercaptomethylergo line) from acid 9,10-dihydrolysergic is herein disclosed. The process can be carried out without isolating most intermediates and is particularly convenient both from the yield and safety standpoint. Moreover, pergolide thereby obtained is highly pure and can be conveniently transformed into pergolide mesylate.

FIELD OF THE INVENTION

The present invention relates in general to ergot alkaloids, inparticular to a process for the synthesis of pergolide 1 from9,10-dihydrolysergic acid.

TECHNOLOGICAL BACKGROUND

Pergolide 1 (D-6-n-propyl-8-βmethylmercaptomethylergoline) is asemisynthetic ergot alkaloid (produced by a fungus of genus Claviceps,Claviceps purpurea) used for the therapy of Parkinson's disease.

In particular, pergolide mesylate 2, a strong agonist of dopaminergicreceptors, is used in therapy.

The usual starting product for the synthesis of pergolide is lysergicacid 3 (D-6-methyl-8β-carboxy-9-ergolene), which can be obtained byfermentation.

U.S. Pat. No. 4,166,182 discloses a synthesis of pergolide (scheme 1)which comprises conversion of lysergic acid intoD-6-n-propyl-8β-hydroxymethylergoline 4, derivatization of the hydroxygroup with methanesulfonyl chloride and reaction with sodiumthiomethoxide. The resulting pergolide can then be salified withmethanesulfonic acid.

Compound 4 is obtained (scheme 2) by catalytic reduction of lysergicacid 3 to 9,10-dihydrolysergic acid 6, esterification of the acidicfunction and reduction of ester 7 with NaBH₄. The resulting compound 8,known as dihydrolysergol or 8,9-dihydroelimoclavine, is demethylated atthe nitrogen in position 6 (following, for example, the proceduredisclosed in U.S. Pat. No. 3,901,894 or the procedure disclosed in J.Pharm. Sci. 1981, 70, 1319-21), to give D-8β-hydroxymethylergoline 9,which is alkylated, for example, with propyl iodide in the presence ofbases.

The key-intermediate of this pathway, dihydrolysergol 8, can also beobtained from elimoclavine, another fermentation product of Clavicepspurpurea, by means of catalytic reduction, according to U.S. Pat. No.3,901,894.

Alternatively, compound 4 can be obtained (scheme 3) by demethylation ofester 7 (obtained as described above) and by acylating with propionylchloride the nitrogen in position 6; the treatment of compound 11 withLiAlH₄, which at the same time reduces the ester and the amidicfunction, affords compound 4.

Even though these synthetic approaches allow to obtain highly purepergolide, they require recovery of a number of intermediates, whichdetermines poor yields (not higher than 20%) and makes the processestime-consuming and unsafe.

A more convenient synthesis in terms of yields has been disclosed byMisner in U.S. Pat. No. 5,465,060; the method allows to prepare“one-pot” pergolide from dihydrolysergol 8 (scheme 4), by demethylationof quaternary ammonium salts with nucleophiles, according to Hutchins eDu (J. Org. Chem. 1973, 38, 1961-2). Dihydrolysergol 8 is transformedinto an intermediate quaternary ammonium salt 12 by treatment withpropyl iodide, whose alcoholic hydroxy group is subsequently derivatizedwith methanesulfonyl chloride to give an intermediate of formula 13. Thetreatment with sodium thiomethoxide allows, at the same timedemethylation of the quaternary nitrogen and formation of the thiomethylether. Despite a reduced number of steps and high yields (above 70%),the resulting pergolide is contaminated by some ergolinic impurities,which cannot be removed by conventional crystallization. For this reasontwo chromatographic purification steps are necessary, one of them withpreparative HPLC [W. Misner et al., Org. Process Res. Dev. (1997) 1,77-80], which require the use of highly toxic solvents, such asacetonitrile and chloroform [J. H. Kennedy, Org. Process Res. Dev.(1997) 1, 68-71] and increase the risk of exposure to the final product.

DETAILED DISCLOSURE OF THE INVENTION

It has now been found that the demethylation of quaternary ammoniumsalts with nucleophiles can be conveniently exploited for the synthesisof pergolide via intermediate 4 from 9,10-dihydrolysergic 6 acid.

The process of the present invention (scheme 5) comprises the followingsteps:

-   -   a) reaction of 9,10-dihydrolysergic acid 6 with propyl iodide to        give D-6-methyl-6-n-propyl-8 B-propyloxycarbonyl-6-ergolinium        iodide 14;    -   b) reduction of intermediate 14 to give        D-6-methyl-6-n-propyl-8β-hydroxymethyl-6-ergolinium iodide 12;    -   c) demethylation of intermediate 12 with nucleophiles to give        D-6-n-propyl-8β-hydroxymethylergoline 4;    -   d) reaction of intermediate 4 with alkylsulfonyl halides or        toluenesulfonyl halides to give        D-6-n-propyl-8β-alkylsulfonyloxymethylergoline or        D-6-n-propyl-8β-tosyloxymethylergoline 5;    -   e) reaction of compound 5 with sodium thiomethoxide to give        pergolide 1.

The reduction reaction is carried out according to conventional methods,preferably using metal hydrides, more preferably sodium borohydride.

The nucleophiles used for the demethylation of the salt of formula 12are alkaline thioalkoxides, preferably sodium, lithium or potassiumthioalkoxides; more preferably the demethylating agent is sodiumthiomethoxide or sodium 2-mercaptoethoxide.

The alkylsulfonyl halides and the toluenesulfonyl halides have theformula RSO₂X, in which R is a straight or branched C₁-C₃ alkyl chain,or the group C₆H₅CH₂—, whereas X is a halogen selected from fluorine,chlorine, bromine, iodine. According to a preferred embodiment of theinvention, the alkylsulfonyl halide is methanesulfonyl chloride.

Pergolide obtained according to the present invention can beconveniently transformed into pergolide mesylate according to knownmethods.

Intermediate 14 is a novel compound and is also object of the presentinvention.

Method A

According to a first preferred embodiment of the invention the processis carried out as follows.

Step a

Tipically 9,10-dihydrolysergic acid 6 is reacted with 3.2-6.0equivalents of 1-iodopropane, preferably 4-5 equivalents, in thepresence of a base, until complete conversion of the starting productinto D-6-methyl-6-n-propyl-8β-propyloxycarbonyl-6-ergolinium iodide 14.The reaction is carried out at 60-90° C., preferably at 75-80° C., in asolvent selected from N-methylpyrrolidone, hexamethylphosphoramide,dimethylpropyleneurea and dimethylethyleneurea. 2.5-10 Volumes ofsolvent are used, preferably 4-5 volumes, with respect to the weightamount of 9,10-dihydrolysergic acid. The base is preferably an inorganicbase, more preferably bicarbonate or carbonate anions, in an amountpreferably ranging from 2.5 to 3.0 equivalents.

The reaction can be monitored by HPLC, using a C18 silica column, elutedwith a phosphate buffer-acetonitrile mixture. After completion of thereaction (generally the conversion is complete within 10-12 hours at 75°C.) the solution of the salt 14 is cooled to room temperature anddiluted with a solvent selected from N-methylpyrrolidone,hexamethylphosphoramide, dimethylpropyleneurea and dimethylethyleneurea.Preferably, 1-5 volumes of solvent are used (with respect to the finalvolume of the reaction mixture), more preferably 2-3 volumes.

Step b

The solution from step a) is heated to 25-50° C., preferably to 30-40°C., and the synthesis is continued by adding 0.5-3.5 equivalents,preferably 1.0-2.0 equivalents, of alkaline-earth ions, such as calciumor magnesium, and 6-16 equivalents, preferably 8-10 equivalents, of areducing agent, preferably sodium borohydride (in both cases the amountis referred to the starting 9,10-dihydrolysergic acid). The mixture isreacted at 40-50° C., preferably at 45° C., until complete conversion ofintermediate 14 into salt 12.

Step c

The demethylation of salt 12 is carried out by adding 5-20 equivalents,preferably 10-12 equivalents, of a nucleophile agent as defined above,preferably sodium thiomethoxide in a commercial 21% aqueous ormethanolic solution. The reaction mixture is kept at 60-90° C.,preferably at 70-80° C., until disappearance of ammonium salt 12. Duringthe reaction, the water or methanol deriving from the commercial sodiumthiomethoxide solution evaporate. Once the reaction is complete, if acommercial 21% methanolic sodium thiomethoxide solution has been used,the mixture is concentrated until complete removal of the methanol andthe residue is taken up with the same volume of water as that beforeevaporation, then 0.2-1.0 volumes of an organic solvent and again onevolume of water are added. The organic solvent is an ester, preferablymethyl isobutyl ketone, ethyl acetate or n-butyl acetate, or ahalogenated organic solvent, preferably methylene chloride. According toa particularly preferred embodiment of the invention the solvent isethyl acetate. The mixture is stirred for 15-20 minutes at roomtemperature and the phases are separated. The aqueous phase is extractedwith one volume of the same organic solvent and the two phases areseparated. The organic phases are pooled, washed twice with one volumeof water and concentrated to {fraction (1/10)}-{fraction (1/20)} of thestarting volume. 0.2-1 Volumes (with respect to the volume before theconcentration) of solvent are added and the mixture is concentratedagain to {fraction (1/10)}-{fraction (1/20)} of the starting volume.Addition and concentration are repeated once, then a solvent selectedfrom pyridine, picoline, lutidine in an amount ranging from 5 to 8volumes, preferably from 6 to 7 volumes, is added.

Step d

After cooling to a temperature ranging from −10° C. to 50° C.,preferably from −10° C. to 0° C., an alkylsulfonyl halide, preferablymethanesulfonyl chloride, or a toluenesulfonyl halide, in an amountranging from 1.0 to 3.0 equivalents, preferably from 1.5 to 2.0equivalents (with respect to the starting 9,10-dihydrolysergic acid) isslowly dropped to the mixture from step c), under inert atmosphere. Themixture is reacted until complete disappearance ofD-6-n-propyl-8β-hydroxymethylergoline 4. After completion of thereaction compound 5 is precipitated by addition of 0.2-0.8 volumes of15% ammonium hydroxide and 1-3 volumes of water; the product is filteredand dried under vacuum at 40-70° C. for 10-30 hours. Compound 5 has a97.5-98.0% purity; in the case of compound 5a, for example, the mainimpurity is D-6-methyl-8β-mesyloxymethylergoline (HPLC percentage area:2.0-2.5%).

Compound 5 is further purified according to conventional chromatographictechniques. Compound 5 is dissolved in 8-12 volumes of mixtures of twoorganic solvents selected from alcohols and organic halogenatedsolvents, preferably methanol/dichloromethane.

More preferably, compound 5 is not essiccated, but dried by means ofdissolution in 10-20 volumes of a halogenated organic solvent,preferably dichloromethane, followed by evaporation. The solvent isrepeatedly added and evaporated, until the water in the solution amountsto less than 0.5%. The product is dissolved in a mixture of two organicsolvents selected from alcohols and halogenated organic solvents,preferably methanol/dichloromethane. The solution is adsorbed on 10-100volumes of normal phase silica, then eluted with organic solventsselected from esters, methyl isobutyl ketone, ethyl acetate or n-butylacetate, preferably ethyl acetate, alcohols, methanol, ethanol,isopropanol, preferably methanol and organic halogenated solvents,preferably dichloromethane, and binary and ternary mixtures thereof.Other solvents known in the literature can also be used. The fractionscontaining pure compound 5 are pooled and concentrated to {fraction(1/10)}-{fraction (1/20)} volume; a solvent selected fromN-methylpyrrolidone, hexamethylphosphoramide, dimethylpropyleneurea anddimethylethyleneurea, in an amount ranging from 10 to 50 volumes,preferably 20-30 volumes, with respect to compound 5, is added and thesolution is further concentrated to remove the residues of the solventsused in the purification.

Step e

The solution from step c) is added with 5-20 equivalents, preferably10-12 equivalents, of sodium thiomethoxide in commercial 21% methanolicsolution, at a temperature ranging from 0° C. to 80° C., preferably from20 to 30° C., and the solution is concentrated under vacuum to distilmethanol off. The reaction is monitored by HPLC until completedisappearance of compound 5. After completion of the reaction (30-60′ at25° C.), 1-3 volumes of water (with respect to the starting volume ofthe synthesis of the pergolide) are added and complete precipitation ofpergolide 1 is observed with negligible losses in the mother liquors.The product is dried at 40-70° C. for 10-30 hours.

Method B

According to a second, even more preferred embodiment of the invention(hereinafter referred to as “method B”), steps a)-e) are carried out asfollows.

Step a

Tipically 9,10-dihydrolysergic acid 6 is reacted with 3.2-6.0equivalents of 1-iodopropane, preferably 4-5 equivalents, in thepresence of a base, until complete conversion of the starting productinto D-6-methyl-6-n-propyl-8β-propyloxycarbonyl-6-ergolinium iodide 14.The reaction is carried out at 60-90° C., preferably at 75-80° C., in asolvent selected from N-methylpyrrolidone, hexamethylphosphoramide,dimethylpropyleneurea and dimethylethyleneurea. 2.5-10 Volumes ofsolvent are used, preferably 4-5 volumes, with respect to the weightamount of 9,10-dihydrolysergic acid. The base is preferably an inorganicbase, more preferably bicarbonate or carbonate anions, in an amountpreferably ranging from 2.5 to 3.0 equivalents.

The reaction can be monitored by HPLC, using a C18 silica column, elutedwith a phosphate buffer-acetonitrile mixture. Generally the conversionis complete within 10-12 hours at 75° C.

Step b

The solution from step a) is heated to 25-65° C., preferably to 45-60°C., and the synthesis is continued by adding 0.5-3.5 equivalents,preferably 1.0-2.0 equivalents, of alkaline-earth ions, such as calciumor magnesium, and 2-10 equivalents, preferably 3-5 equivalents, of areducing agent, preferably sodium borohydride (in both cases the amountis referred to the starting 9,10-dihydrolysergic acid) dissolved in 1-5volumes, preferably 2-3 volumes (with respect to the initial amount of9,10-dihydrolysergic acid) of a solvent selected fromN-methylpyrrolidone, hexamethylphosphoramide, dimethylpropyleneurea anddimethylethyleneurea. The mixture is reacted at 45-60° C., preferably at55° C., until complete conversion of intermediate 14 into salt 12.

Step c

The reaction mixture from step b) is added with 5-20 equivalents,preferably 14-16 equivalents, of an inorganic strong base, preferablysodium hydroxide, and is added with 5-20 equivalents, preferably 14-16equivalents, of a nucleophile as defined above, preferably withcommercial 2-mercaptoethanol. The mixture is kept at 60-90° C.,preferably at 65-75° C., until disappearance of the salt 12. Aftercompletion of the reaction compound 4 is recovered by crystallizationfrom an EDTA aqueous solution and an alkaline or alkaline-earth metalchloride aqueous solution, preferably a KCl or NaCl aqueous solution,most preferably a NaCl aqueous solution. More precisely, the reactionmixture is added of 0.1-0.5 volumes (with respect to the volume of thereaction mixture) of methanol, 1-3 volumes, preferably 1.5-2.5 volumes,of an EDTA aqueous solution at a concentration of 20-100 g/l, preferably40-60 g/l, adjusted to pH 10-14, preferably to pH 12-13, with aninorganic base as defined above, 1-3 volumes, preferably 1.5-2.5volumes, of an NaCl aqueous solution at a concentration of 200-350 g/l,keeping the temperature at 60-90° C., preferably at 65-75° C. Themixture is subsequently cooled down to 0-25° C., preferably to 5-10° C.The product is filtered and washed with an EDTA aqueous solution at aconcentration of 20-100 g/l, preferably 40-60 g/l, adjusted to pH 10-14,preferably to pH 12-13, with an inorganic base as defined above, andsubsequently washed with deionized water. Compound 4 has a 98.5-99.0%purity; the main impurity is compound 8 (HPLC percentage area:0.8-1.3%). The humid product is dissolved in 20-50 volumes (with respectto the product's volume), preferably 30-40 volumes, of an organic estersolvent, preferably methyl isobutyl ketone, ethyl acetate or n-butylacetate, or an organic halogenated solvent, preferably methylenechloride. More preferably, the solvent is ethyl acetate. The resultingsolution is evaporated to half volume and added with half volume of thesame organic solvent. Evaporation and addition are repeated 1-4 times,preferably 2-3 times.

The last organic solvent aliquot is evaporated until {fraction(1/10)}-{fraction (1/20)} of the starting volume, thereafter a solventselected from pyridine, picoline, lutidine in an amount ranging from 5to 8 volumes, preferably from 6 to 7 volumes is added.

Step d

The mixture from step c) is cooled down to a temperature ranging from−50° C. to 10° C., preferably from −10° C. to 0° C. and thetoluenesulfonyl halide or the alkanesulfonyl halide, preferablymethanesulfonyl chloride, is slowly dropped thereto, under inertatmosphere, in an amount ranging from 1.0 to 3.0 equivalents, preferablyfrom 1.5 to 2.0 equivalents (with respect to the starting9,10-dihydrolysergic acid). The mixture is reacted until completedisappearance of D-6-n-propyl-8β-hydroxymethylergoline 4. Aftercompletion of the reaction compound 5, for exampleD-6-n-propyl-8β-mesyloxymethylergoline 5a, is precipitated by additionof 0.2-0.8 volumes of 15% ammonium hydroxide and 1-3 volumes of water;the product is filtered and washed with 5-10 volumes of deionized water.Compound 5a has a 98.5-99.0% purity, the main impurity beingD-6-methyl-8β-mesyloxymethylergoline (HPLC percentage area 0.4-0.7%).

Humid compound 5 is dissolved in 20-50 volumes (with respect to theproduct volume), preferably 30-40 volumes, of an organic ester solvent,preferably methyl isobutyl ketone, ethyl acetate or n-butyl acetate,more preferably ethyl acetate. The resulting solution is evaporated tohalf volume and added with one volume of the same organic solvent.Evaporation and addition are repeated 1-4 times, preferably 2-3 times.The last aliquot of organic solvent is evaporated to {fraction(1/10)}-{fraction (1/20)} of the starting volume. A solvent selectedfrom N-methylpyrrolidone, hexamethylphosphoramide, dimethylpropyleneureaand dimethylethyleneurea, in an amount ranging from 10 to 50 volumes,preferably 15-30 volumes with respect to compound 5, is added and thesolution is further concentrated to remove the previous solvent.

Step e

The solution from step d) is added with 1-10 equivalents, preferably 2-4equivalents, of solid sodium thiomethoxide, at a temperature rangingfrom −10° C. to 50° C., preferably from 0 to 5° C. The reaction ismonitored by HPLC until complete disappearance of compound 5. Aftercompletion of the reaction (60-90′ at 5° C.), the mixture is heated to40-90° C., preferably 70-80° C., and added with 0.5-3 volumes,preferably 1-1.5 volumes of deionized water (with respect to the finalvolume of the reaction mixture): precipitation of pergolide 1 isobserved. When the dropping is over the mixture is cooled to roomtemperature. The slurry is filtered and the losses in the mother liquorrange from 0.5 to 1.5%. The product is dried at 40-70° C. for 10-30hours. Compound 1 has a 99.8-99.9% purity; the major impurity isD-6-methyl-8β-methylthiomethylergoline (HPLC percentage area lower than0.1%).

For the synthesis of pergolide mesylate 2, pergolide is mixed with 10-25volumes of methanol, preferably with 12-15 volumes, or humid pergolidebase is used. The solution is heated to 40-64° C., preferably to 50-60°C., and 1-1,1 equivalents of methanesulfonic acid are added. Thesolution is concentrated to half volume and one volume of a solventselected for example from isopropanol, acetone and water, preferablyisopropanol, is added and concentrated again to half volume. The mixtureis cooled down to room temperature, filtered and dried under vacuum at40-70° C. for 10-30 hours.

The quality of the resulting pergolide mesylate complies with therequirements of the European Pharmacopoeia.

The process of the present invention is particularly advantageous inthat it can be carried out without isolating most of the intermediates.In particular, method A can be carried out without isolating theintermediates of formula 14, 12 and 4; this determines higher yields(higher than 80% compared with 9,10-dihydrolysergic acid) and highersafety. Moreover, the recovery of compound 5, which is remarkably moresoluble compared with pergolide, allows to use less toxic solvents andto carry out a single chromatographic purification step on silica gel.

Method B is even more convenient, because it does not make recovery ofintermediates 14 and 12 necessary and does not require cromatographicpurification. In fact, hot-crystallization from water of compound 4 andpergolide 1 allows to significantly reduce the main impurities, inparticular dihydrolysergol 8 which derives from the demethylation ofcompound 12. If not removed, compound 8 would co-precipitate and reactin the subsequent steps, thus forming other impurities, such as thosementioned above.

A further advantage of the invention consists in that the demethylationof the quaternary salt 12 and the nucleophilic substitution which leadsto pergolide can be carried out using a commercial sodium thiomethoxidesolution, which does not have to be neutralized, as in Misner'sprocedure. According to Misner's procedure sodium thiomethoxide isprepared by dissolving methylmercaptan in the solvent(N-methylpyrrolidone) at low temperature (−10° C.) and subsequentlysalifying with NaOH; as an alternative, the commercial solution,pre-treated with methylmercaptan to remove excess of base, can be used.

A further advantage of the invention consists in that the demethylationof the quaternary salt 12 can also be conveniently carried out using thecommercial 2-mercaptoethanol solution which, differently from sodiumthiomethoxide, does not generate any toxic gas.

The process of the present invention is moreover particularlyadvantageous because it allows to obtain highly pure pergolide,sufficiently high not to require further purification of the derivedsalts (such as mesylate) in order to comply with the requirements of theEuropean Pharmacopoeia.

The invention will be now illustrated in more detail by means of someexamples.

EXAMPLES Example 1

Step a), Method A and Method B: Conversion of 9,10-dihydrolysergic Acid6 into D-6-methyl-6-n-propyl-8β-propyloxycarbonyl-6-ergolinium Iodide 14

In a multiple neck, round-bottom flask, 9.3 grams of9,10-dihydrolysergic acid (0.0344 moles) are added under nitrogenatmosphere to 40 ml of N-methylpyrrolidone at room temperature, followedby 8.67 g of sodium bicarbonate (0.103 moles) and 30.4 g of n-propyliodide (0.179 moles). The mixture is heated to 80° C. and reacted forabout 10 hours.

The reaction can be monitored by HPLC using a C18 Hypersil columnequipped with a 280 nm detector and eluted with 50:50phosphate:acetonitrile buffer.

At the end of the reaction the starting product is completely convertedinto intermediate 14.

Example 2

Step b), Method A: Conversion of D-6-methyl-6-n-propyl8β-propyloxycarbonyl-6-ergolinium Iodide 14 intoD-6-methyl-6-n-propyl-8β-hydroxymethyl-6-ergolinium Iodide 12

The solution from example 1 is cooled down to 25° C., diluted with 120ml of N-methylpyrrolidone and heated to 35° C. After addition of 5 g(0.0451 moles) of CaCl₂ and 6.5 g (0.172 moles) of NaBH₄, the mixture isheated at 45° C. for 1 hour. At the end of the reaction intermediate 14is completely transformed into intermediate 12.

Step b), Method B: Conversion of D-6-methyl-6-n-propyl8β-propyloxycarbonyl-6-ergolinium Iodide 14 intoD-6-methyl-6-n-propyl-8β-hydroxymethyl-6-ergolinium Iodide 12

The solution from example 1 is cooled down to 45° C. and added of 5 g(0.0451 moles) of CaCl₂ and of 6.5 g (0.172 moles) of NaBH₄ dissolved in45 ml of N-methylpyrrolidone. The mixture is heated at 55° C. for 1hour. At the end of the reaction intermediate 14 is completelytransformed into intermediate 12.

Example 3

Step c), Method A: Conversion ofD-6-methyl-6-n-propyl-8β-hydroxymethyl-6-ergolinium Iodide 12 intoD-6-n-propyl-8β-hydroxymethylergoline 4

The solution from example 2 is added with 185 ml of CH₃SNa (0.524 moles)in commercial 21% methanolic solution. The mixture is heated to 80° C.and reacted at the same temperature for about 3-4 hours distillingmethanol off the reaction mixture.

The reaction can be monitored by HPLC using a C18 Hypersil columnequipped with a 280 nm detector and eluted with 75:25 phosphate buffer:acetonitrile.

At the end of the reaction intermediate 12 is completely converted intoD-6-n-propyl-8β-hydroxymethylergoline 4 (about 98%) andD-6-methyl-8,8-hydroxymethylergoline 8 (about 2%). The suspension isthen concentrated under vacuum by means of a rotary evaporator untilmethanol is completely removed. The suspension is then added with 130 mlof deionized water. After addition of 300 ml of ethyl acetate, themixture is stirred for 15-20 minutes, then the organic phase isseparated. The aqueous phase is added with further 300 ml of ethylacetate, stirred for 15-20 minutes and the organic phase is separated.The organic phases are pooled (total volume: about 600 ml) and washedtwice with 600 ml of deionized water, then concentrated under vacuum to30 ml with a rotary evaporator. Ethyl acetate (100 ml) is added and thesolution is concentrated again to 30 ml. After addition of 160 ml ofethyl acetate and concentration to 15 ml, 100 ml of pyridine are added.

Step c), Method B

The solution from Example 2 is added with 20.6 g of NaOH (0.516 moles)and with 40.4 g of HO—CH₂CH₂—SH (0.516 moles), heated to 70° C. andreacted at 70° C. for about 7-10 hours.

The reaction can be monitored by HPLC using a C18 Hypersil column elutedwith 75:25 phosphate buffer: acetonitrile equipped with a 280 nmdetector.

At the end of the reaction intermediate 12 is completely transformedinto D-6-n-propyl-8β-hydroymethylergoline 4 (about 98%) anddihydrolysergol 8 (about 2%).

The suspension is added with 30 ml of methanol and slowly added with 370ml of 52 g/l disodium EDTA solution adjusted to pH 13 with NaOH, keepingthe temperature at 70° C. NaCl (270 ml, 300 g/l) is then droppedthereto, keeping the temperature at 70° C., thereafter the mixture isslowly cooled down to 5° C. The product is filtered and washed firstwith 15 ml of 52 g/l disodium EDTA solution adjusted to pH 13 with NaOH,then with 100 ml of deionized water and dried in a static dryer undervacuum at 60° C. for 20 hours. 8.6 grams of dry product with 99%D-6-n-propyl-8β-hydroymethylergoline purity and with aD-6-methyl-8β-mesyloxymethylergoline content of 0.5% are obtained (otherimpurities: 0.5%). The humid D-6-n-propyl-8β-hydroymethylergoline 4crystals are dissolved in 240 ml of ethyl acetate and the solution isconcentrated under vacuum to 120 ml with a rotary evaporator. Ethylacetate (120 ml) is added and the solution is concentrated again to 120ml. After addition of a further 120 ml ethyl acetate aliquot, thesolution is concentrated to 15 ml and added with 100 ml of pyridine.

Example 4

Step d), Method A: Conversion of D-6-n-propyl-8β-hydroxymethylergoline 4into D-6-n-propyl-8β-mesyloxymethylergoline 5a

The solution from example 3 is cooled down to −5° C. and 5.9 g (0.0515moles) of methanesulfonyl chloride are slowly dropped thereto, keepingthe temperature below 0° C. The mixture is reacted for 1 hour. Thereaction can be monitored by HPLC using a C18 Hypersil column equippedwith a 280 nm detector and eluted with 50:50 phosphatebuffer:acetonitrile.

At the end of the reaction the conversion ofD-6-n-propyl-8β-hydroxymethylergoline 4 intoD-6-n-propyl-8β-mesyloxymethylergoline 5a is complete. Once the reactionis completed 60 ml of 15% ammonium hydroxide and 190 ml of deionizedwater are added and the mixture is stirred for 15-20′ and filtered. Theproduct is washed on the filter with 100 ml of deionized water and driedin a static dryer under vacuum at 60° C. for 20 hours. 10.8 grams of dryproduct with 97% D-6-n-propyl-8β-mesyloxymethylergoline purity and 2%D-6-methyl-8β-mesyloxymethylergoline purity are obtained (otherimpurities: 1%).

Step d), Method B

The solution from Example 3 is cooled down to −5° C. and 5.9 g (0.0515moles) of methanesulfonyl chloride are slowly dropped thereto, keepingthe temperature below 0° C. The mixture is reacted for 1 hour.

The reaction can be monitored by HPLC with a C18 Hypersil column elutedwith 50:50 phosphate buffer:acetonitrile equipped with a 280 nmdetector.

At the end of the reaction, i.e. whenD-6-n-propyl-8β-hydroxymethylergoline is completely transformed intoD-6-n-propyl-8β-mesyloxymethylergoline, 60 ml of 15% ammonium hydroxideand 190 ml of deionized water are added. The mixture is stirred for15-20′ and filtered. The product is washed on the filter with 100 ml ofdeionized water and dried in a static dryer under vacuum at 60° C. for20 hours. 10.5 Grams of dry product with 99%D-6-n-propyl-8β-mesyloxymethylergoline purity and 0.5%D-6-methyl-8β-mesyloxymethylergoline are obtained (other impurities0.5%).

Example 5

Purification of D-6-n-propyl-8β-mesyloxymethylergoline 5a, Method A

The dry product obtained according to Example 4 (10.8 g) is dissolved in100 ml of a 10:90 methanol:dichloromethane mixture. The solution isadsorbed over 500 g of silica gel conditioned with a 80:10:10 ethylacetate:dichloromethane:methanol mixture and eluted with the samemixture. 20 Fractions 50 ml each are collected and analysed by HPLC; thefractions which contain pure 5a (A % HPLC>99.9%) are pooled,concentrated to 30 ml by means of a rotary evaporator and added with 220ml of N-methylpyrrolidone.

Example 6

Step e) (Method A): Conversion of D-6-n-propyl-8β-mesyloxymethylergoline5a into Pergolide 1

The solution from example 5 is kept at 25° C. and added with 100 ml(0.284 moles) of CH3SNa in commercial 21% methanolic solution. Thesolution is concentrated by means of a rotary evaporator until methanolis completely removed. The reaction is monitored by HPLC using a C18Hypersil column equipped with a 280 nm detector and eluted with 50:50phosphate:acetonitrile buffer. At the end of the reaction compound 5a iscompletely converted into pergolide 1. Deionized water (350 ml) isadded, the mixture is filtered and the product is washed with 100 ml ofdeionized water. The product is dried in a static dryer under vacuum at60° C. for 20 hours. 8.64 grams of dry product with 99.9% D-6-n-propyl-8p-methylthiomethylergoline purity are obtained.

Step e) Method B

The humid crystals of D-6-n-propyl-8β-mesyloxymethylergoline 5a fromexample 4 are dissolved in 240 ml of ethyl acetate. The solution isconcentrated under vacuum to 120 ml with a rotary evaporator. Ethylacetate (120 ml) is added and the solution is concentrated again to 120ml. After addition of a further 120 ml ethyl acetate aliquot, thesolution is concentrated to 15 ml and added with 50 ml ofN-methylpyrrolidone.

The resulting solution is kept at 0° C. and added with 4 g (0.058 moles)of solid CH₃SNa. The reaction is monitored by HPLC with a C18 Hypersilcolumn equipped with a 280 nm detector and eluted with 50:50 phosphatebuffer: acetonitrile At the end of the reaction compound 5a iscompletely transformed into pergolide 1. N-methylpyrrolidone (170 ml) isadded and the solution is heated to 75° C. Deionized water (286 ml) isdropped thereto, keeping the temperature at 75° C., then the mixture iscooled to room temperature and filtered. The product is washed with 100ml of deionized water at 75° C. The product is dried in a static dryerunder vacuum at 60° C. for 20 hours. 8.4 grams of dry product with 99.8%D-6-n-propyl-8β-methylthiomethylergoline purity and 0.1%D-6-methyl-8β-methylthiomethylergoline purity are obtained.

Example 7

Salification of Pergolide 1 into Pergolide Mesylate 2 (Method A and B)

8.64 grams (0.0275 moles) of pergolide 1 from example 6 are suspended in130 ml of methanol at room temperature. The suspension is heated to 60°C. and added with 2.70 grams (0.0281 moles) of methanesulfonic acid in15% methanolic solution. The resulting solution is evaporated to 55 ml,added with 60 ml of isopropanol and concentrated again to 55 ml. Themixture is allowed to cool down to 25° C. and filtered. The crystalproduct on the filter is washed twice with 50 ml of isopropanol. Theproduct is dried in a static dryer under vacuum at 60° C. for 24 hours.

10.45 grams of pergolide mesylate 2 with quality complying with theEuropean Pharmacopoeia standards (EP suppl. 2001) are obtained (molaryield from 9,10-dihydrolysergic acid to pure pergolide mesylate: 74%).

1. A process for the synthesis of pergolide 1

comprising the following steps: a) reaction of 9,10-dihydrolysergic acid6

with propyl iodide to giveD-6-methyl-6-n-propyl-8(3-propyloxycarbonyl-6-ergolinium iodide 14;

b) reduction of intermediate 14 to giveD-6-methyl-6-n-propyl-8(3-hydroxymethyl-6-ergolinium iodide 12;

c) demethylation of intermediate 12 with nucleophiles to giveD-6-n-propyl-8(3-hydroxymethylergoline 4;

d) reaction of D-6-n-propyl-8β-hydroxymethylergoline 4 with analkylsulfonyl halide or a toluenesulfonyl halide RS02X, in which R is astraight or branched Cl—C alkyl chain, or a C6HSCH2 residue, whereas Xis a halogen selected from fluorine, chlorine, bromine and iodine togive D-6-n-propyl-8β-alkylsulfonyloxymethylergoline orD-6-npropyl-8(3-tosyloxymethylergoline 5, in which R has the meaningsdefined above;

e) reaction of compound of formula 5 with sodium thiomethoxide to givepergolide
 1. 2. A process as claimed in claim 1) in which steps b), c)and d) are carried out without recovering intermediates 14, 12 and
 4. 3.A process as claimed in claim 1) in which compounds 4, 5 and 1 arerecovered by crystallization.
 4. A process as claimed in claim 3) inwhich steps b) and c) are carried out without recovering intermediates14 and
 12. 5. A process as claimed in claim 1 in which before step e)the compound 5 is purified by chromatography.
 6. A process according toclaim 1 in which the reduction of step b) is carried out with metalhydrides.
 7. A process as claimed in claim 6) in which the metal hydrideis sodium borohydride.
 8. A process according to claim 1 in which thedemethylation of step c) is carried out with alkaline thioalkoxides. 9.A process as claimed in claim 8) in which alkaline thioalkoxides aresodium, potassium or lithium thioalkoxides.
 10. A process as claimed inclaim 9) in which the thioalkoxide is sodium thiomethoxide.
 11. Aprocess as claimed in claim 9) in which the thioalkoxide is sodium 202-mercaptoethoxide.
 12. A process as claimed in claim 1 in which thealkylsulfonyl halide is methanesulfonyl chloride.
 13. A process asclaimed in claim 3 in which compound 4 from step c) is recovered fromthe reaction mixture by crystallization with an EDTA aqueous solutionand an alkaline or alkaline-earth metal chloride aqueous solution at atemperature ranging from 60 to 90° C.
 14. A process as claimed in claim3) in which pergolide 1 from step e) is recovered from the reactionmixture by crystallization with water at a emperature ranging from 40 to90° C.
 15. The quaternary salt of formula 14.